Subjects with acute renal failure (ARF), chronic kidney disease (CKD), or end stage renal disease (ESRD) may experience moderate to severe malfunction of the nephron, the smallest functional unit of the kidney. For example, in CKD, the nephrons may still be partially functional, but as the disease progresses this function declines, and if the glomerular filtration rate is less than 10% of normal levels, the disease has progressed to ESRD. Critically ill subjects with ARF may have relatively high mortality rates, for example, between about 50% and about 70% for subjects admitted to hospitals. In addition, ARF subjects are typically dependent on hemodialysis or hemo filtration for survival.
The glomerulus is an important component of the kidney, and the structure of the glomerulus determines its permselectivity, where large and/or negatively charged molecules are prevented from passing across the glomerulus, unlike small and/or positively charged molecules. Such properties enable uremic substances, such as creatinine and urea, together with water, glucose, and ions to permeate across the glomerulus as an ultrafiltrate, and at the same time allow for the retention of blood cells and larger proteins within the circulatory system. The ultrafiltrate that is produced flows across the tubule of the nephron, whereby biological reabsorption of certain molecules back into the circulatory system occurs. The selective biological reabsorption of water, glucose, and ions is performed by an epithelium cell layer that lines the tubules. In addition, the epithelium of the proximal tubule secretes xenobiotics and drugs into the glomerular filtrate, which often cannot be efficiently cleared by glomerular filtration. Furthermore, the epithelium of the proximal tubule can help to control the pH of blood by resorption of bicarbonate. The epithelium also has important metabolic and endocrinologic functions. Molecules that are not reabsorbed are removed from the body as urine. Failure of the mechanical filtration or tubular functions, provided by the glomerulus or tubules respectively, could result in clinical complications, such as ARF, CKD, or ESRD.
With prolonged life expectancy, the ratio of subjects with CKD or ESRD that requires organ replacement to the number of suitable donors has increased. To enhance the survival rate of these subjects, hemodialysis treatment has been employed to artificially replace the mechanical filtration function of glomerulus. Polymeric membranes with open interconnected pores, in the form of hollow fibers, are often used in these dialyzers where they function as a sieving medium with carefully controlled pore sizes. This treatment is generally administered to subjects 3 or 4 times a week for 2 to 4 hours of treatment. Although successful, prolonged intermittent treatment may be detrimental over the long term due to hemodynamic instability as a result of large shift of solutes and fluids over a short period of time. In addition, it does not replace the lost reabsorption, metabolic, secretory, or endocrine functions of the tubules. Dialyzers used for hemodialysis therefore replace kidney function only incompletely, and are thus not an ideal treatment for subjects with ARF, CKD, or ESRD.
Recently, investigators have combined cellular functions within such mechanical devices to create bioartificial kidneys (BAKs). For example, bioartificial kidneys containing functional kidney cells have been developed to provide the cellular functions of tubules. BAK treatments may decrease the mortality rates of critically ill subjects having ARF. BAKs typically contain a synthetic hemo filter connected in series with a bioreactor cartridge containing porous membranes, onto which cells such as renal proximal tubule cells are seeded. Within the dialyzers conventionally used for BAKs are typically thousands of hollow fiber membranes arranged in parallel. These membranes are usually fabricated from polysulfone (PS) or polyethersulfone (PES), a PS variant that is low in protein retention. In typical BAK systems, cells such as primary human kidney proximal tubule cells (HPTCs) adhere, proliferate, and function on the polymeric membranes, which now also play the part of a cellular scaffold. However, HPTCs cultivated on these substrates have typically produced mixed results.
Primary human renal proximal tubule cells (HPTCs) have been used for clinical applications of BAKs. Such tubule cells form a simple epithelium in vivo, and perform a variety of transport, metabolic, endocrinologic, and probably also immunomodulatory functions. Transport functions of such cells include the reabsorption of glucose, small solutes, and bicarbonate from the glomerular filtrate, as well as the transport of toxins, xenobiotics, and drugs into the tubular lumen. In order to perform such functions efficiently in a BAK, however, the HPTCs must form a well-differentiated epithelium with a controllable degree of leakiness on the porous membranes. It can be difficult to seed HPTCs on suitable membrane surfaces for use in BAK systems, and/or to cause such HPTCs to form a suitable differentiated structure.
In addition and more generally, applications involving or requiring growth and differentiation of cells adhered on solid surfaces, for example in the context of bioimplants and bioartificial organs, often require expensive or difficult to manufacture materials for cell immobilization to facilitate both growth/maintenance and cell differentiation, if growth and differentiation is achievable at all. The inability of many solid materials conventionally used in and readily available for medical applications to support the growth and differentiation of certain cells seeded thereon and the difficulty of certain conventional surface modification and coating techniques in overcoming this shortcoming has been a problem in field of bioartificial organ/bioimplant design and in other fields/applications where the differentiation of cells immobilized on an artificial and/or manufactured surface is desirable.
Accordingly, improvements in such techniques are needed.